A stenosis is a stricture of a canal or duct. In the context or the vascular system a stenosis is a narrowing of the lumen of a blood vessel. A stenosis can severely restrict blood flow and promote thrombosis which can lead to myocardial infarction or stroke, for example. A common type of primary stenosis is artherosclerotic plaque. Several therapeutic methods have been developed to improve circulation and hemostasis in stenotic vessels including by-pass surgery and revascularization procedures. Revascularization procedures (e.g., balloon angioplasty, atherectomy, rotorary ablation (rotoblation)) serve to improve blood flow by reducing or removing the stenosis. However, these procedures frequently injure the blood vessel. The biological response to the injury is a multifactorial fibro-proliferative process that is similar to wound healing, and includes the elaboration of growth factors from a variety of cell types, infiltration of leukocytes, migration and proliferation of smooth muscle cells, the production of extracellular matrix and tissue remodeling (Anderson, Vessels, 2:4-14 (1996)). The process can result in the formation of a thick neointima within the vessel wall which reduces the luminal area of the vessel (i.e., restenosis). Restenosis occurs following about 20-50% of coronary angioplasty procedures (Anderson, Vessels, 2:4-14 (1996)).
Attempts have been made at reducing restenosis following vascular intervention procedures by, for example, administering pharmacologic agents and placement of endovascular stents. However, although stents are reported to partially reduce restenosis (Serruys, et al., N. Engl. J. Med., 331:489-495 (1994)), restenosis and in-stent restenosis remain a significant problem. Therefore, a need exists for new methods for inhibiting stenosis and restenosis.
The invention relates to a method of inhibiting stenosis or restenosis of a blood vessel following vascular injury. In one embodiment the method comprises administering to a subject in need thereof, a therapeutically effective amount of a first therapeutic agent which inhibits the adhesion and/or recruitment of neutrophils to a site of vascular injury, and a therapeutically effective amount of a second therapeutic agent which inhibits the adhesion and/or recruitment of mononuclear cells to a site of vascular injury. In a certain embodiment, the method is a method of inhibiting stenosis or restenosis following vascular injury which occurs during or is caused by a therapeutic or diagnostic vascular intervention procedure (e.g., angiography, angioplasty, vascular by-pass surgery, vascular grafting, endarterectomy, atherectomy, endovascular stenting, insertion of prosthetic valve and transplantation of organs, tissues or cells). The first and second therapeutic agents can independently be an antagonist of a cellular adhesion molecule or an antagonist of chemokine receptor function, for example. In certain embodiments, the first therapeutic agent binds to an integrin (e.g., a xcex22 integrin) and inhibits integrin-mediated cellular adhesion. Preferably, the first therapeutic agent binds CD18 and inhibits binding of one or more ligands (e.g., ICAM-1, ICAM-2, ICAM-3, fibrinogen, C3bi, Factor X) to a CD18 containing integrin. In additional embodiments, the second therapeutic agent is a chemokine receptor antagonist. Preferably, the second therapeutic agent can bind CCR2 and inhibit the binding of a ligand (e.g., MCP-1, MCP-2, MCP-3, MCP-4, MCP-5) to the receptor. In preferred embodiments, the first and second therapeutic agents are antibodies or antigen-binding fragments thereof.
In a more particular embodiment, the method is a method of inhibiting stenosis or restenosis in a subject following percutaneous transluminal coronary angioplasty (PTCA). In another particular embodiment, the method is a method of inhibiting stenosis or restenosis in a subject following a vascular intervention procedure which includes placement of a stent. In another embodiment, the method of inhibiting stenosis or restenosis in a subject following vascular injury comprises administering to a subject in need thereof, an effective amount of an agent which inhibits recruitment and/or adhesion of neutrophils and mononuclear cells to a site of vascular injury.
The invention further relates to an agent that inhibits recruitment and/or adhesion of neutrophils or mononuclear cells to sites of vascular injury (e.g. cellular adhesion molecule antagonists (e.g., anti-CD18 antibodies), antagonists of chemokine receptor function (e.g., anti-CCR2 antibodies)) for use in therapy (including prophylaxis) or diagnosis, for example, as described herein, and to the use of such an antagonist for the manufacture of a medicament for the inhibition of stenosis or restenosis. The invention also relates to a medicament for the inhibition of stenosis or restenosis (e.g., following a vascular intervention procedure (e.g., angioplasty, percutanious transluminal coronary angioplasty) wherein said medicament comprises an agent that inhibits recruitment and/or adhesion of neutrophils or mononuclear cells to sites of vascular injury (e.g. cellular adhesion molecules antagonists (e.g., anti-CD18 antibody), antagonist of chemokine receptor function (e.g., anti-CCR2 antibody)).